Project Summary The fastest growing demographic at risk of, and suffering from dementia, is the oldest-old, persons over age 80 or 90 years. By 2030, 1 in 2 incident cases of Alzheimer dementia (AD) will likely occur in this age group. The underlying biology and the impact of vascular and lifestyle risk factors on risk of dementia appear to be different in the young-old and oldest-old. Further, these factors likely interact with each other, with the impact of early and midlife risk exposure as reflected by the state of the brain (on MRI) when individuals enter old age (age 655 years), and with the multiple systemic illnesses that also manifest with aging. There is however, limited longitudinal data on the same individuals, followed for over 10-25 years from their 60s to their 80s and beyond. We propose a Cross-Cohort collaboration (CCC) across 8 large population studies (the Framingham Heart Study (FHS), The Cardiovascular Health Study (CHS), the Age, Genes/ Susceptibility study- Reykjavik, (AGES-RS), the Three Cities study (3C), the Rotterdam Study (RS), the Atherosclerosis Risk in Communities study (ARIC), the Austrian Study of Stroke Prevention (ASPS) and the Study of Health in Pomerania (SHIP). These studies, which obtained brain MRI and cognitive assessments between 1990-2001, continue to follow participants, and collectively have over 15,000 participants in whom initial brain MRI and cognitive assessments were obtained prior to age 70 and subsequent cognitive, dementia status and/or MRI assessments have been obtained until they died, developed dementia, or reached an age of 80+ free of dementia. These participants also have detailed, repeated assessments of vascular, metabolic and lifestyle risk factors, stroke, and the health of other organ systems at and after age 60 years, and after age 80 yrs. Finally, over 27,000 participants have cognition data beyond age 80 (>5000 with MRI) to study the proximate and remote determinants of incident dementia and AD in the oldest-old. We propose the following aims: Aim 1: To relate various measures such as established and novel MRI markers of brain injury (infarcts, WMH, microbleeds, hippocampal volumes, cortical atrophy patterns, microinfarcts, enlarged perivascular spaces etc.) dysfunction or disease in other organ system, and vascular, metabolic, social and lifestyle measures, gathered at age 60-70 to probability of reaching age 85 (+/- 5) years alive and dementia free. Aim 2 (a-c): To relate the same MRI, organ function and risk factors examined in Aim 1, as recorded at ages 60-70 and 70-80 to probability of developing clinical dementia after age 80. Aim 3: To examine if, how, and to what extent systemic organ dysfunction and risk factors beyond age 60 modified the association between brain injury markers and probabilities of cognitively healthy aging versus clinical dementia in the oldest-old. Aim 4: To examine if key AD related genes (such as APOE, BDNF, BIN1) modify the associations seen in Aims 1 and 2, or the interactions explored in Aim 3. Our findings will facilitate more effective, targeted efforts at prevention of dementia in the oldest-old, a key component of any public health strategy to reduce AD burden and costs.